PERSPECTIVEpublished: 21 December 2015

doi: 10.3389/fmicb.2015.01460

Edited by:Ian Marriott,

University of North Carolinaat Charlotte, USA

Reviewed by:Hajime Hisaeda,

Gunma University, JapanAnn-Kristin Mueller,

University Hospital Heidelberg,Germany

*Correspondence:Kevin C. Kain

kevin.kain@uhn.ca

†Co-first authors

Specialty section:This article was submitted to

Microbial Immunology,a section of the journal

Frontiers in Microbiology

Received: 01 May 2015Accepted: 07 December 2015Published: 21 December 2015

Citation:McDonald CR, Tran V and Kain KC

(2015) Complement Activationin Placental Malaria.

Front. Microbiol. 6:1460.doi: 10.3389/fmicb.2015.01460

Complement Activation in PlacentalMalariaChloe R. McDonald1,2†, Vanessa Tran1† and Kevin C. Kain1,3*

1 Sandra Rotman Laboratories, Sandra Rotman Centre for Global Health, Toronto General Research Institute, UniversityHealth Network, Toronto, ON, Canada, 2 Department of Global Health and Population, Harvard School of Public Health,Boston, MA, USA, 3 Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, University of Toronto,Toronto, ON, Canada

Sixty percent of all pregnancies worldwide occur in malaria endemic regions. Pregnantwomen are at greater risk of malaria infection than their non-pregnant counterparts andhave a higher risk of adverse birth outcomes including low birth weight resulting fromintrauterine growth restriction and/or preterm birth. The complement system plays anessential role in placental and fetal development as well as the host innate immuneresponse to malaria infection. Excessive or dysregulated complement activation hasbeen associated with the pathobiology of severe malaria and with poor pregnancyoutcomes, dependent and independent of infection. Here we review the role ofcomplement in malaria and pregnancy and discuss its part in mediating altered placentalangiogenesis, malaria-induced adverse birth outcomes, and disruptions to the inutero environment with possible consequences on fetal neurodevelopment. A detailedunderstanding of the mechanisms underlying adverse birth outcomes, and the impact ofmaternal malaria infection on fetal neurodevelopment, may lead to biomarkers to identifyat-risk pregnancies and novel therapeutic interventions to prevent these complications.

Keywords: malaria, pregnancy, placental malaria, complement, inflammation, angiogenesis, neurodevelopment

THE GLOBAL BURDEN OF MALARIA

Nearly half of the world’s population remains at risk of malaria infection (WHO, 2013).Malaria is caused by the protozoan parasite Plasmodium and includes five species that infecthumans: Plasmodium falciparum, P. vivax, P. ovale, P. malaria, and P. knowlesi. Among these,P. falciparum causes the most severe disease and accounts for the majority of malaria-associateddeaths (Dellicour et al., 2010). Pregnant women are particularly susceptible to malaria-associatedmorbidity and mortality with approximately 125 million pregnancies at risk of infection eachyear (Dellicour et al., 2010). Malaria during pregnancy can result in anemia, stillbirth, andlow birth weight (LBW) resulting from intrauterine growth restriction (IUGR) and/or pretermbirth (PTB; Rogerson et al., 2003; Umbers et al., 2011; Eisele et al., 2012). These outcomesare associated with an increased risk of neonatal mortality and contribute to an estimated200 000 infant deaths annually (Steketee et al., 2001; van Geertruyden et al., 2004). PTB,IUGR, and LBW have consistently been associated with developmental delay and an increasedrisk of long-term health consequences including cardiovascular disease, diabetes, and obesity(March of Dimes, PMNCH, Save the Children, WHO, 2012; Visentin et al., 2014). Further, agrowing body of evidence has linked in utero exposure to infections to long-term cognitiveand behavioral disorders including autism, schizophrenia, and depression (Knuesel et al.,2014). Despite the connection between prenatal infections and adverse neurological outcomes

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for the developing child, the potential impact of in uteroexposure to malaria on subsequent neurodevelopment remainsunderstudied.

PATHOPHYSIOLOGY OF PLACENTALMALARIA

Plasmodium falciparum infection during pregnancy can resultin placental malaria (PM), defined by the accumulation ofparasitized erythrocytes (PEs) in the placental intervillousspace and the infiltration of maternal monocytes/macrophages(Rogerson et al., 2003). The PEs that sequester in the placentabind via a unique P. falciparum erythrocyte membrane protein1 (PfEMP1) variant, VAR2CSA, to the glycosaminoglycanchondroitin sulfate A (CSA) that is expressed on thesyncytiotrophoblast lining of the intervillous space (Duffyet al., 2006; Mens et al., 2010; Clausen et al., 2012). As such,protective immunity developed during exposure to malariain non-pregnancy is ineffective such that primigravidae areat highest risk of PM and its associated poor birth outcomes(Desai et al., 2007). Adaptive immunity is gradually acquiredduring malaria infections in pregnancy and is mediated by theacquisition of anti-VAR2CSA adhesion blocking and opsonicantibodies (Fried et al., 1998; Desai et al., 2007; Keen et al., 2007).

Sequestration of PEs stimulates maternal macrophages toexpress β-chemokines, including monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, andMIP-1β, that recruit other inflammatory mediators and initiatethe inflammatory cascade (Suguitan et al., 2003). This localizedplacental immune response and inflammation is thought tocontribute to the adverse birth outcomes associated with PM.Although the precise mechanisms of placental and fetal injury areunclear, evidence suggests that the complement system may playa role.

THE COMPLEMENT SYSTEM

The complement system is a crucial immune surveillance andinnate defense pathway. It is composed of both soluble andmembrane bound proteins that cooperate to function in hostdefense and inflammation. Normally, the complement systemis maintained at a basal level of activation but can be furtheramplified through three major activation pathways: the classicalpathway, the mannose-binding lectin (MBL) pathway, and thealternative pathway (Ricklin et al., 2010; Wagner and Frank,2010; Woodruff et al., 2011). The classical pathway is activatedby binding of C1q to IgM or IgG immune complexes, themannose-binding lectin pathway is activated by binding offoreign carbohydrate moieties, and the alternative pathway isactivated by bacterial lipopolysaccharide (LPS) and negativelycharged viral surfaces. The three pathways converge in asequential cleavage cascade that results in opsonization-mediatedphagocytosis, cell lysis, or an inflammatory response through theactivation of the C3-convertase, which catalyzes the cleavage ofC3 to C3a and C3b. C3b is an opsonizing fragment that binds

to foreign antigens and increases phagocytosis. In addition, C3bcan combine with C3-convertases to form the C5-convertasewhich cleaves C5 to C5a and C5b. C3a and C5a are potentanaphylatoxins that activate neutrophils and macrophages topromote inflammation. C5b recruits C6–C9 and forms themembrane attack complex (MAC), which can insert in cellmembranes and lyse target cells. In addition to these traditionalpathways, direct C3 and C5 cleavage can occur via thrombin orserine proteases (Huber-Lang et al., 2002; Ward, 2004; Huber-Lang et al., 2006).

The complement system is also an important regulatorof several developmental processes, and as such requirestight regulation to prevent excessive activation (Ricklinand Lambris, 2007; Silver et al., 2010). Regulation iscontrolled through the expression of complement regulatoryproteins including the complement receptor 1 (CR1),decay accelerating factor (DAF), and Factor H. Theseproteins control complement activation by binding effectorproteins to limit activation or to accelerate degradationof complement components (Ricklin et al., 2010). Theimportant role of complement in normal developmentalprocesses is highlighted by several diseases that are linked tomutations in complement effector and regulatory proteinsincluding, systemic lupus erythematosus, age-related maculardegeneration, atypical hemolytic uremic syndrome (aHUS),paroxysmal nocturnal hemoglobinuria (PNH), and deficitsin vascular development and metabolism (Seelen et al., 2003;Edwards et al., 2005; Haines et al., 2005; Klein et al., 2005;Risitano, 2012; Cofiell et al., 2015; Martinez-Barricarte et al.,2015).

COMPLEMENT ACTIVATION INPREGNANCY AND OBSTETRICCOMPLICATIONS

The complement system plays an essential role in healthypregnancies (Regal et al., 2015) protecting against local infectionand regulating the maternal immune response to the semi-allogenic fetal tissue (Richani et al., 2005; Derzsy et al., 2010).During early pregnancy the trophoblast layer invades thedecidua resulting in an inflammatory response controlled bytrophoblast-derived complement regulatory proteins includingmembrane cofactor protein (MCP, CD46), protectin (CD59),and DAF (CD55; Tedesco et al., 1993). The placenta synthesizescomplement components, providing a local source of protectionfrom infection. Histological studies have reported positivestaining for C1q, C9, C3d, C4BP, and Factor H in placentasfrom healthy term pregnancies. Human trophoblast cellssecrete C3 and C4 proteins and phagocytic activity in thetrophoblast is mediated by activated C3 in mouse trophoblastcells (Albieri et al., 1999; Bulla et al., 2009). Endothelialcells in the placenta secrete C1q, which appears at sites oftrophoblast invasion into the decidual tissue (Bulla et al., 2008).Throughout pregnancy regulatory proteins produced by thechorion facilitate complement activity and prevent complement-mediated placental injury.

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Excessive or dysregulated activation of the complementsystem can overwhelm these regulatory and protectivepathways. Multiple studies have reported an associationbetween complement split products (e.g., C3a and C5a) ormutations in complement regulatory proteins and obstetriccomplications (Tedesco et al., 1993; Lynch et al., 2011; Dennyet al., 2013). An estimated 8–18% of women with preeclampsiahave mutations in complement regulatory proteins (Salmonet al., 2011). Increased circulating levels of C5a, activatedFactor B (Bb), C5b-9 and C3a/C3 ratio in pregnancy havebeen linked to spontaneous abortion, preeclampsia, hemolysis,and the elevated liver enzymes, low platelet count (HELLP)syndrome (Girardi et al., 2006a; Derzsy et al., 2010; Lynch andSalmon, 2010). Experimental models have provided mechanisticevidence that blockade of C5a, C5a receptor (C5aR), FactorB, C3, or C6 in non-infection models protects against fetallethality and IUGR (Holers et al., 2002; Girardi et al., 2006b;Lynch et al., 2011; Singh et al., 2011). C5a may contributeto multiple complications in pregnancy via its ability tosynergistically induce the secretion of pro-inflammatory (e.g.,TNF, IL-8, IL-1β) and anti-angiogenic factors (e.g., solublefms-like tyrosine kinase-1 [sFlt-1]) from leukocyte populations(Conroy et al., 2009; Langer et al., 2010). Cleavage of C5 hasalso been reported to induce monocyte recruitment, matrixmetalloprotease production, and cervical ripening in a mousemodel of LPS-induced PTB (Gonzalez et al., 2011, 2013). In thismodel, blocking C5a-C5aR signaling rescued offspring fromcortical fetal brain injury (Pedroni et al., 2014). Finally, sC5b-9in urine has been associated with an anti-angiogenic profileincluding elevated sFlt-1, and reduced placental growth factor(PGF) and vascular endothelial growth factor (VEGF; Gusehet al., 2015).

COMPLEMENT IN PLACENTAL MALARIA

Complement is a key component of the innate immuneresponse to malaria and contributes to both protection(e.g., PE opsonization) and pathologic host responses (e.g.,coagulopathy, inflammation, and endothelial activation; Silveret al., 2010; Biryukov and Stoute, 2014). Activation can occurby both traditional and non-traditional pathways (Figure 1).For example, IgG has been shown to be deposited on thesurface of PEs and C-reactive protein has been shown tobe elevated in malaria infection (Mibei et al., 2005), both ofwhich can activate the classical pathway. Activation of thealternative pathway can occur from parasite-induced alterationsto the erythrocyte surface that induce spontaneous C3 activationor by platelet-derived factor D following vascular damage(Roestenberg et al., 2007). Evidence for MBL pathway activationis inferred from a higher prevalence of MBL polymorphisms(e.g., MBL2.LXPA haplotype) in women with PM, however,no association was observed between levels of MBL andinfection or birth outcomes (Thevenon et al., 2009). Finally,malaria can activate complement through C3-independentpathways through cleavage of C3 and C5 via thrombinand serine proteases released by phagocytic leukocytes or

the parasite (Huber-Lang et al., 2002, 2006; Conroy et al.,2009).

This excessive complement activation during malariainfection can perturb the tight regulation that is importantduring a healthy pregnancy. Research in human populationsand mouse models support the hypothesis that malaria-inducedcomplement activation contributes to adverse birth outcomes byincreasing inflammation and dysregulating angiogenic processesessential for normal placental development and function(Conroy et al., 2011, 2013). Several observational studies havereported elevated C5a in peripheral and placental blood inwomen with PM and linked these changes to adverse birthoutcomes, including IUGR, PTB, and LBW (Conroy et al., 2011).Further, this was associated with dysregulated angiogenesis inthe placenta (Conroy et al., 2009, 2013). Placental and fetalvascular development is regulated by several pathways, mostnotably the VEGF and Angiopoietin-Tie2 pathways (Gevaet al., 2002; Charnock-Jones et al., 2004; Burton et al., 2009).The VEGF axis is essential for placental vascularization, vesselgrowth, and remodeling (Kingdom et al., 2000; Charnock-Jones et al., 2004; Kaufmann et al., 2004). VEGF and otherpro-angiogenic factors in this family, such as PGF, interact withanti-angiogenic mediators (e.g., sFlt-1) to regulate endothelialcell survival, proliferation, migration, and sprouting (Demiret al., 2004, 2006). Malaria-induced complement activation mayresult in a shift to an anti-angiogenic profile (i.e., increasedsFlt-1 and decreased PGF and VEGF) that can impede normalvasculogenic and angiogenic processes (Silver et al., 2011;Conroy et al., 2013). In vitro, C5a, in combination with parasiteproducts, results in the synergistic release of pro-inflammatorymediators and anti-angiogenic factors, including sFlt-1, fromhuman monocytes (Conroy et al., 2009). Complement-inducedanti-angiogenic activity can disrupt these closely regulatedprocesses and provoke changes in the placental vasculature.Genetic and pharmacological blockade of C5a-C5aR increasesplacental vascular length and segment number, reduces vascularresistance in the placenta, and increases fetal weight andviability (Conroy et al., 2013). This rescue is thought to bemediated in part by reducing the impact of C5a on the Ang/Tie2pathway.

The angiopoietins, Ang-1 and Ang-2, are angiogenic factorsthat act in a context-dependent manner with VEGF toregulate placental vasculogenesis, angiogenesis, and vascularinflammation. The angiopoietins competitively bind to the Tie-2 receptor and act as antagonists to one another with Ang-1inducing vascular maturation and Ang-2 causing destabilizationof the vascular network and angiogenesis (Charnock-Jones et al.,2004). Decreased levels of circulating Ang-1 and elevated levelsof Ang-2 were observed in malaria-infected pregnant women inCameroon and Malawi (Silver et al., 2011; Conroy et al., 2013).Further, an increase in the ratio of Ang-2/Ang-1 was observed inCameroonian women who delivered LBW infants and this effectwas recapitulated in the mouse model of PM (Silver et al., 2010).These findings support the role of dysregulated angiogenesisin adverse birth outcomes associated with PM and highlightthe potential for Ang/Tie2-targeted therapies as interventionstrategies.

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FIGURE 1 | Overview of key pathways in placental malaria (PM) and potential targets for therapeutic intervention to improve birth outcomes.Strategies to optimize placental vascular development and function may impact the length of gestation, birth weight, and birth outcome by targeting complementand complement-associated pathways. Inflammation and dysregulation of angiogenic pathways has been observed in association with chondroitin sulfate A(CSA)-binding parasitized erythrocytes (PEs) in the intervillous space of the placenta. Key angiogenic factors such as (1) the angiopoietins (Ang), Ang-1 and Ang-2,which act as antagonists at the Tie-2 receptor and (2) vascular endothelial growth factor (VEGF), mediate vasculogenic and angiogenic processes in the placenta.(3) Malaria-induced complement activation resulting in the cleavage of C5a, a potent anaphylatoxin, contributes to increased inflammation and dysregulatedangiogenesis and can be targeted via anti-C5a antibodies or alternatively, by more cost-effective strategies such as (4) L-arginine supplementation. L-argininesupplementation could increase bioavailable nitric oxide (NO), which acts to reduce malaria-induced inflammation at the maternal-fetal interface and promotevascular development. ICAM, intercellular adhesion molecule; MAC, membrane attack complex; VWF, von Willebrand factor.

POTENTIAL THERAPEUTIC STRATEGIESTARGETING COMPLEMENT ANDASSOCIATED PATHWAYS

Optimizing placental vascular development and function andresulting changes in the in utero environment can impact the

length of gestation, birth weight, and birth outcome. PTB is nowthe leading direct cause of infant mortality and the second leadingcause of death in children under the age of five, after pneumonia(Blencowe et al., 2012; March of Dimes, PMNCH, Save theChildren, WHO, 2012). Maternal infections are considered themajor modifiable factor contributing to PTB, with the highest

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burden occurring in low resource settings. Despite the enormouspublic health impact of malaria in pregnancy, there are feweffective interventions, and even fewer aimed at promotinghealthy placental development. The above pathways highlight keyangiogenic mediators (e.g., Ang/Tie2 and VEGF) altered duringPM that can be investigated as targets for new interventions toimprove birth outcomes in high-risk pregnancies (Figure 1).

Angiogenic-modifying compounds are currently beinginvestigated therapeutically for a number of diseases, includinganti-angiogenic therapies for metastatic cancer, wound healing,and pathological vasculopathies and retinopathies (Huang et al.,2010; Wietecha and DiPietro, 2013; Gacche and Meshram, 2014).Historically, most approaches have targeted VEGF to eitherrestrict (anti-VEGF therapy as cancer therapeutics) or promote(VEGF therapy in wound healing) angiogenesis (Delli Carpiniet al., 2010; Wietecha and DiPietro, 2013). Although earlyclinical trials yielded promising results in tumor stabilizationand improved patient survival, resistance to VEGF-targetedtherapies is emerging (Bergers and Hanahan, 2008; Ebos et al.,2009). Only recently has the Ang/Tie2 pathway been targeted forregulating angiogenesis. In cancer therapies, Tie2 inhibitors andAng-1/-2 traps have been investigated and have shown promisinganti-tumor growth activity in various cancer cell lines and goodtolerability in early human trials (Huang et al., 2010).

Ang/Tie-2-targeted therapeutics have not been investigated inthe context of PM, however, in vivo data using the mouse modelof cerebral malaria have shown potential utility (Serghides et al.,2014). While this has yet to be evaluated in humans, it providesproof-of-principle evidence to support the use of Ang-targetedtherapies. Given the observed decrease in circulating maternalAng-1 and the associated dysregulated placental angiogenesis,therapies that regulate the Ang/Tie2 pathway may have clinicaluse in PM but there are important safety barriers to overcomewith any of these agents.

A humanized monoclonal antibody to complement C5,Eculizumab, is approved to treat aHUS and PNH (Risitano,2012). aHUS shares many pathophysiological features withmalaria including release of free heme, complement activation,and endothelial dysfunction in association with the release ofvWF andAng-2 (Noris et al., 2014). PNH is caused by the reducedexpression of complement regulatory proteins on hematopoieticcells resulting in intravascular hemolysis, thrombophilia, andcytopenias. During pregnancy, patients with PNH are at a greaterrisk of mortality (Ray et al., 2000). Case reports of Eculizumabfor PNH during pregnancy suggest that blockade of C5 signalingdoes not negatively impact birth outcomes (Kelly et al., 2010;Marasca et al., 2010; Patriquin and Leber, 2015). Given thatcomplement is an upstream regulator of angiogenesis and thetrials of anti-C5 antibody in pregnancy report good tolerability,the use of anti-complement strategies to treat PM is promising(Figure 1). However, the high cost of anti-complement antibodieswould limit its use in resource-constrained settings and thereforemore affordable strategies need to be explored. For example, L-arginine is an essential amino acid in pregnancy and immediateprecursor of nitric oxide (NO), an endogenous regulator ofplacental vascular development (Goodrum et al., 2003; Krauseet al., 2011). There is substantial evidence that malaria-infection

depletes L-arginine and greatly reduces bioavailable NO andthat this contributes to the pathobiology of severe malaria(Anstey et al., 1996; Lopansri et al., 2003; Serghides et al.,2011; Weinberg et al., 2014). Low dietary intake of L-arginineis common in resource-constrained settings and further depletesbioavailable NO. L-arginine supplementation in pregnancymay promote placental vascular development and function byrestoring bioavailable NO (Figure 1). Intervention strategiestargeting the L-arginine-NO pathway are being discussed aspotential therapeutics for preeclampsia and appear promisingdue to simple routes of administration, low cost, and a verylow toxicity profile in pregnancy (Cindrova-Davies, 2014; Johalet al., 2014). Given the number of pregnancies at risk of malariainfection, in combination with the rising rates of PTB particularlyin low resource settings, L-arginine supplementation may presenta safe, affordable, and feasible intervention to reduce malariaimmunopathology and protect the in utero environment.

THE IMPACT OF MALARIA ONNEUROCOGNITIVE DEVELOPMENT OFOFFSPRING

It is well established that normal placental development isfundamental to optimal fetal growth. In addition to PM-induced changes in vascular development, malaria infectionmay interfere with complement-mediated pathways that regulateneurodevelopment in utero (Figure 2). Research has highlightedthe pivotal role that the prenatal environment plays in postnatalneurodevelopment as well as later life cognition and behavior(Bilbo and Schwarz, 2009; Bale et al., 2010; Mwaniki et al.,2012). The impact of prenatal infection on neurodevelopmentalprocesses has been examined in animal models and in children(Deverman and Patterson, 2009; Khandaker et al., 2012).Maternal viral and bacterial infections have been linked toincreased risk of developmental delay, schizophrenia, autism,bipolar disease, and paraventricular leukomalacia (Ellman andSusser, 2009; Parboosing et al., 2013). However, to date littleis known about the role of maternal malaria infection onin utero neurodevelopment. It is estimated that 200 millionchildren under the age of five in low and middle-resourcesettings are not reaching their developmental potential as aresult of exposure to environmental factors that negatively impactearly neurocognitive development, including a prominent rolefor malaria infection (Grantham-McGregor et al., 2007). Thecomplement system may be a common pathway involved in theregulation of healthy placental and fetal development as well as inutero neurodevelopmental processes.

Most complement components and receptors are expressedby astrocytes, microglia and neurons in the CNS (O’Barret al., 2001; Veerhuis et al., 2011) and the role of thecomplement system in neurodegenerative processes has beenwell studied (Bonifati and Kishore, 2007; Woodruff et al.,2011; Orsini et al., 2014). Complement activation has beenlinked to neuro-inflammation in several neurodegenerativedisorders including stroke, Parkinson’s disease, and Alzheimer’sdisease (Zanjani et al., 2005; Banz and Rieben, 2012; Pavlovski

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FIGURE 2 | Proposed mechanism of PM-mediated adverse birth outcomes and altered neurodevelopmental processes. PM is characterized bysequestration of PEs in the intervillous space of the placenta resulting in the recruitment of leukocytes (monocytes and macrophages), complement activation, andlocalized inflammation (A). We propose that this localized maternal inflammation induces an inflammatory and complement response in the fetus (B). Subsequently,induced complement activation and dysregulation of complement effector and regulatory proteins impact neurodevelopmental processes by altering brain cytokinelevels, dysregulating angiogenic processes, and altering normal synaptic pruning (C). Initiation of the complement cascade induces maternal inflammation which canresult in the presence of inflammatory mediators in the fetal brain. Complement may also impact fetal cerebral vascular development and dependentneurodevelopmental pathways. Finally, increased levels of complement can lead to excessive elimination of synapses and disrupt refinement of precise neural circuitsthat are critical to normal fetal neurodevelopment. Adapted from McDonald et al. (2013) Trends in Parasitology 29(5) 213–219. Adapted with permission.

et al., 2012). Complement-mediated recruitment and activationof glial cells, which secrete cytokines and free radicals, candisrupt neuronal function and induce neurotoxicity (Zanjaniet al., 2005; Ager et al., 2010). While any specific role ofthe complement system in fetal neurodevelopmental processesremains unknown, it has recently been linked with numerousearly neurodevelopmental processes including neurogenesis,cell migration, and synaptic pruning (Rahpeymai et al., 2006;Chu et al., 2010; Stephan et al., 2012; Pedroni et al.,2014).

Research in our laboratory using a mouse model of PM,has observed impaired learning and memory, and increaseddepressive-like behavior in offspring born to malaria-infecteddams. This correlated with reduced regional levels of major

biogenic amines (dopamine, serotonin and norepinephrine) inthe frontal cortex, temporoparietal cortex, and the striatum.The behavioral phenotype and reduction in circulating levels ofneurotransmitters was rescued by genetic and pharmacologicalblockade of signaling via the C5a-C5aR pathway (McDonaldet al., 2015). Importantly, these results were observedindependent of a birth phenotype (LBW or PTB). In the absenceof infection-induced LBW, the inflammatory pathways inducedby maternal infection can result in a fetal inflammatory response,altered angiogenesis, and changes in synaptic development thatcan impact in utero and postnatal neurodevelopmental processes(Figure 2). While the specific role that the complement systemplays in fetal neurodevelopment continues to be elucidated,this research has important implications for malaria as many

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exposed pregnancies do not result in a birth phenotype but maystill be at risk of adverse neurodevelopmental outcomes.

CONCLUSION

The majority of all pregnancies worldwide are at risk ofmalaria infection (Dellicour et al., 2010). These pregnancies

occur in low resource settings where the burden of adversebirth outcomes is greatest. Based on the fundamental rolethe complement system plays in the regulation of immune,vascular and central nervous system development, wepropose that the complement system plays a central rolein the pathology, adverse birth outcomes, and potentialneurocognitive impairments resulting from malaria infectionin pregnancy.

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Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.

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